Project 3 takes postmortem neurotransmitter findings in suicides with MDD and radioligand development of the last five years and brings them together in a fashion that is best done with in vivo positron emission tomography (PET). We and others find abnormalities of the serotonergic system, principally the serotonin IA receptor (5-HTIA ) and serotonin transporter (5-HTT) postmortem in depressed suicides. We have pilot PET data indicating that low 5-HTT binding in the same brain regions as suicides in MDD suicide attempters compared with MDD nonattempters and healthy volunteers. This indicates a potential suicide-related biological endophenotype in suicides that may be detectable in MDD before the first suicide attempt. In this project we seek to determine whether this is an endophenotype that is present before the first suicide attempt or onset of MDD, and its relationship to childhood adversity. We have found that 5-HTT binding is lower in depressed patients with reported childhood adversity. Rodent studies indicate that early adversity alters 5-HTIA binding. Specifically, we hypothesize that [11C]DASB 5-HTT binding will be low in MDD attempters and childhood adversity will contribute to this effect. With our new agonist 5-HTIA radiotracer, [11C]CUMI-101, we predict higher 5-HTIA agonist binding in MDD attempters as seen in suicides. We hypothesize that the 5-HTIA and 5-HTT binding in MDD suicide attempters, compared with MDD nonattempters and controls, will parallel findings in suicides. Both PET tracers will be used in the same groups to determine which tracer is best to detect differences between the groups, and these data will be used by Dr. Ogden in P6. To determine if this is a potential endophenotype, we will scan a group of high-risk offspring of MDD attempters before their first suicide attempt or episode of MDD. In the last two years of the project we will study new neurotransmitter targets to expand our knowledge base about suicidal behavior. We will determine monoamine oxidase A (MAOA) levels in healthy volunteers and MDD suicide attempters. MAOA is upregulated in MDD and responsible for the degradation of synaptic serotonin, DA and NE. In the same patients/controls as for MAOA, we will evaluate the endogenous opioid neurotransmitter system, by quantifying the kappa opiod receptor. In collaboration with other Cores and Projects, we will examine the relationship between the binding measures, fMRI responses during appraisal, stress responses, aggressive traits and the effects of reported childhood adversity.